Methods and compositions for treating erectile dysfunction

ABSTRACT

Methods are provided for increasing libido and/or treating erectile dysfunction in a man. The methods include the administration of a formulation testosterone alone, another fast-acting drug to treat erectile dysfunction or a combination of the testosterone and the other drug where at least one is delivered by aersolization. The formulation is preferably aerosolized and inhaled into a patient&#39;s lungs where particles of testosterone and/or the fast-acting erectile dysfunction drug deposits on lung tissue and then enter the patient&#39;s circulatory system.

CROSS-REFERENCES

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/813,100 filed on Mar. 19, 2001, to be issued as U.S. Pat.No. 6,632,419 which is a continuation-in-part of U.S. patent applicationSer. No. 09/563,773 filed on May 2, 2000, now issued U.S. Pat. No.6,428,769 and claims the benefit of U.S. Provisional Patent ApplicationSer. No. 60/132,472 filed on May 4, 1999, all of which are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates generally to methods of treating sexualdysfunction in humans. Such methods include treating women with adecreased libido, treating men with reduced libido and/or having adecreased level of serum testosterone, and treating men having erectiledysfunction. More specifically, the invention relates to acute, bolusnon-invasive administration of testosterone to enhance libido and/or adrug formulation to treat erectile dysfunction over a discrete period oftime.

BACKGROUND OF THE INVENTION

The presence of a normal amount of libido, defined as the urge to engagein sexual activity, is an important component of an individual'swell-being. In both men and women the primary naturally occurringhormone responsible for libido is testosterone. In males, the baselinetestosterone level is a relatively constant throughout life, decreasingslowly in old age. Abnormally low levels of testosterone also occur inmale hypogonadism and are similarly associated with lack of libido andinability to produce or sustain erections. In contrast, women elaboratetestosterone only as part of the process of ovulation. Each maturingfollicle produces testosterone at the mid-point of the menstrual cycle,consistent with observations that female libido peaks with ovulation. Asa woman ages, the number of maturing follicles per month decreases, andthere is a decreasing total amount of testosterone produced. A commoncomplaint of post-menopausal women is decreased libido. This decrease inlibido is characterized by a lack of interest in sexual intercourse, thelack of ability to achieve orgasm, or decrease in intensity of orgasm.It is important to note that this decrease in libido is often associatedwith a profound sense of loss of a once normal and active interest insexual activity. Low levels of testosterone in, e.g., hypogonadal menare associated with lack of libido and absence of erections. Theyrespond to therapy with exogenous testosterone (Cunningham et al., JClin Endocrinol Metab, (March 1990) 70:792-7; Behre et al., J ClinEndocrinol Metab, (November 1992) 75:1204-10; and women also respond totestosterone therapy, see Tuiten et al., Arch. Gen. Phychiatry,(February 2000) 57:149-153.

Clinicians frequently confronted with the problem of managing femalepatients presenting with decreased libido have limited tools to addressthe problem. Testosterone is available as an oral preparation and can begiven, for instance, in combination with estrogen to restoretestosterone levels. However, the replacement of the once pulsatileendogenous delivery of testosterone with the sustained blood level ofthe hormone produces unwanted side effects. Women taking testosteronefor a few weeks typically begin to complain of the emergence ofsecondary sexual characteristics such as unwanted body hair, oily hair,and, with prolonged a use, deepening voice. For this reason, oraltestosterone replacement therapy is not a practical solution for mostpatients with decreased libido.

Other forms of testosterone replacement therapy for women are beingexplored. A transdermal patch capable of delivering a steady rate oftestosterone is being tested for use in women. As with oral testosteronereplacement therapy, the study state blood levels of testosteroneproduced via transdermal delivery are likely to be associated with thesame side effect profile issues.

It is recognized that testosterone in males and females decreases withage (Expert Opin. Pharmacother 2003 February; 4(2):183-90; HumanBiology, May 1980, Vol. 52, No. 2, pages 181-0191), and that sexualmotivation in men with low testosterone as well as mood and well-beingin post-menopausal women is associated with the levels of exogenouslyintroduced testosterone (Psychosomatic Medicine volume 47, No. 4, 1985).Further, providing intravenous testosterone to men and women as part ofclinical studies is known (Am Heart J 2002 February; 143(2):249-56;American Journal of Obstetrics and Gynecology, December 1986 pages 1288to 1292).

Various formulations of testosterone are currently commerciallyavailable to treat sexual dysfunction in men. A transdermal patch formen is sold by Alza Corporation under the name of Testoderm®. Aninjectable for intramuscular injectable is sold by Bristol-Meyers SquibbCompany under the name Delatestryl®, and by Star under the name Virilon®IM. While these dosage forms may increase steady state levels oftestosterone in men, they do not result in the physiologically correctpulsatile release that occurs in men with normal testosteroneproduction. A bolus delivery of testosterone provides an approximationto the pulsatile delivery yielding short brief peaks that can providethe physiological stimulus for increase of sexual desire and improvederectile function.

Current therapies and those under development for erectile dysfunction(ED) include phosphodiesterase (PDE) inhibitors (e.g., Viagra(sildenafil), Clalis), dopamine receptor agonists (e.g., apomorphine),melanocortin receptor agonists, intracavernous therapies (e.g.,alprostadil, papaverine, phentolamine, vasoactive intestinal peptide),growth hormone-releasing peptide receptor agonists, 5-hydroxytryptamine(5-HT; serotonin) receptor agonists, alpha-adrenoceptor antagonists,topical therapies (e.g., alprostadil), guanylyl cyclase activators,rho-kinase antagonists and inhibitors of neuropeptide Y.

In cases where a single therapy for ED is ineffective, combinationtherapy may be effective, especially when two or more mechanisms thedrugs affect different sites of action are simultaneously employed. Forexample, the combination of a drug that acts centrally, e.g., on thecentral nervous system (CNS), with a drug that acts peripherally hasbeen proposed (Andersson and Hedlund, Int. J. Impot. Res. 14(Supp1.1):S82-S92, 2002). For example in a rat model, the erectile response toapomorphine, which acts via the CNS, has been prolonged by sildenafil,which acts peripherally (Andersson et al, J. Urol. 161: 1707-12, 1999).The use of a combination therapy involving inhaled testosterone, whichacts on the CNS, with any other class of treatment, whether it actscentrally or peripherally, having therapeutic potential may be moreeffective than either treatment alone.

SUMMARY OF THE INVENTION

The present invention provides for various methods of treating sexualdysfunction in humans, including reduced libido in women, reduced libidoin men, and erectile dysfunction in men.

In one embodiment, a method is provided for increasing the libido of awoman over a discrete period of time (e.g., 30-240 minutes) by theadministration of testosterone. This method does not maintaintherapeutic levels of testosterone over long periods, e.g., days, weeksor months. Because the method of the invention only maintainstherapeutic levels over a short period, the adverse side effects oflong-term testosterone treatment are avoided.

In another embodiment, a method is provided for increasing libido and/ortreating erectile dysfunction in a man by the administration oftestosterone or another drug formulation including, but not limited to,sildenafil, including sildenafil citrate and other salts of sildenafilas well as other drug formulations and combinations of testosterone,sildenafil, and/or other drugs.

The testosterone formulation used with the present invention may becomprised of a reduced version of testosterone having been reduced by5α-reductase to 5γ-dihydroxytestosterone which is delivered in a bolusdose. The testosterone formulation may be administered in a variety ofdifferent ways, e.g., may be aerosolized preferably producing particleswhich have a size in a range of from about 1 to 3 microns which can beinhaled into areas of the lung where they can readily enter the bloodstream.

With the methods of the present inventions, an aerosol containing a drugis inhaled into the lungs of a patient. Once inhaled, particles of thedrug deposit on lung tissue and from there enter the patient'scirculatory system and thereby increase the patient's serum testosteronelevel. In certain embodiments, the aerosol comprises testosterone or itsreduced version 5-γ-dihydrotestorone. The percentage increase in thepatient's testosterone level will vary depending on the needs of thepatient. However, the patient's normal baseline serum testosterone levelis preferably increased 25% or more and more preferably 100% or more. Bypreferably providing the testosterone in a reduced form, i.e.,5α-dihydroxytestosterone because the delivery is by inhalation thepatient's serum level of an active form of the hormone is quickly raisedto a desired level, e.g., in thirty minutes or less, more preferablyfifteen minutes or less. When the patient's blood serum level of theactive form of the hormone is raised to a desired level the patient'slibido is increased. The increased level gradually subsides (as thehormone is metabolized and cleared) thereby avoiding the adverse sideeffects generated by maintaining enhanced hormone levels over longperiods. Where the aerosol comprises a drug for treating erectiledysfunction, the effect of the drug is realized in less time than whendelivered by other routes of administration such as oral, and preferablyis realized in less than 30 minutes, more preferably in less then 20minutes, still more preferably in less than 10 minutes.

An aspect of the invention is a method of increasing the libido of anadult human female patient by the administration of a bolus dose oftestosterone which quickly increases the level of testosterone in thepatient for a relatively brief time.

Another aspect of the invention is a method of treatment wherebytestosterone or derivative thereof is aerosolized, inhaled and providedto the circulatory system of the patient at levels sufficient toincrease libido (over a short period of time) and propensity for orgasm.

Another aspect of the invention is to combine bolus delivery oftestosterone with additional treatment such as a topical cream appliedto the vaginal area to increase blood flow to that area.

An advantage of the invention is that the testosterone levels are raisedwithin minutes of administration (preferably 30 minutes or less) andreturn to normal levels within hours—preferably in less than four hours.

Another advantage is that the administered testosterone is quicklymetabolized allowing the patient's testosterone levels to return tonormal thereby avoiding the adverse effects of long-term administration.

Another advantage of the invention is that erectile dysfunction andsexual dysfunction are treated more rapidly, as compared to otherdelivery routes, e.g., orally or transdermally, due to the rapidabsorption of small molecules through the lung when inhaled, in orderthat the user need not plan ahead before engaging in sexual activity

Another advantage of the invention that the total dose of erectiledysfunction and sexual dysfunction compounds delivered can be reducedbecause of the rapid absorption from the lung, which will lead toefficacious plasma levels for shorter periods of time, as compared toother administration by other means, e.g., oral and transdermaldelivery. This will allow for reduction in side effects, and cost oftherapy

Another advantage is that the time to onset of action will beindependent of the amount and time of prandial intake.

A feature of the invention is that aerosolized particles of testosteronehaving a diameter of about 0.5 to 8 microns (preferably 1-3 microns) arecreated and inhaled deeply into the lungs thereby enhancing the speedand efficiency of administration.

It is an object of this invention to describe the utility of deliveringtestosterone or dihydrotestosterone by inhalation as a means of treatingwomen with decreased libido and/or decreased propensity to have orgasms.

It is another object of this invention to describe liquid formulations(which includes suspensions) of testosterone and derivatives thereofsuch as 5α-dihydrotestosterone appropriate for pulmonary delivery.

It is another object of this invention to describe how testosterone ordihydrotestosterone delivered via the lung can quickly increase plasmalevels substantially beyond baseline levels for the patient.

It is another object of this invention to describe the blood levels oftestosterone or dihydrotestosterone required for rapid onset of a normalto enhanced libido in men or women with baseline decreased libido.

It is another object of this invention to describe the time course ofinhalation of testosterone or dihydrotestosterone and the onset ofincreased libido in women or men suffering from decreased libido.

It is another object of this invention to describe how the pulsatiledelivery of testosterone or specifically dihydrotestosterone asreplacement therapy for women with decreased libido is associated with adecreased incidence of side effects (secondary sexual characteristics)commonly associated with traditional testosterone replacement therapywhich produces a steady state level of the hormone.

It is another object of this invention to provide men with a pulsatiledelivery of testosterone which approximates the natural physiologicalrelease of testosterone, in contrast to the existing delivery systemsfor testosterone such as transdermal patches or long acting injectionscontaining esters of testosterone.

Other aspects of the invention include bolus (i.e., fast delivery andshort acting effects) delivery of testosterone by any means includingnasal delivery, rapid transdermal delivery which may be with absorptionenhancers, and/or abrasive transdermal systems, microneedle systems, andtopical creams, which systems may be used in various combinations.

The delivery of testosterone by inhalation provides, for the first time,the means for non-invasively delivering clinically relevant amounts oftestosterone on demand near the time of planned intercourse.

It is an object of the invention to provide a method of treatment oferectile dysfunction in a patient comprising the steps of aerosolizing aformulation comprising sildenafil-citrate or other salts of sildenafil,e.g., acetate, or other composition, inhaling the aerosolizedformulation into the lungs of a patient, and allowing the particles ofsildenafil citrate to deposit on lung tissue and enter the patient'scirculatory system.

It is an object of the invention to provide an aerosolized formulationcomprised of sildenafil citrate or another salt of sildenafil, e.g.,acetate, or other composition, and a carrier, the aerosol comprisingparticles having a diameter in the range of about 1.0 micron to 5.0microns, making up 50% or more of the aerosol particles.

It is an object of the invention to provide a kit comprising an aerosoldelivery device and a formulation comprising a testosterone ortestosterone derivative (DHT), sildenafil citrate or other salts ofsildenafil, or other compositions suitable for the treatment of sexualdysfunction or erectile dysfunction, or a combination thereof.

It is an object of the invention to provide a kit comprising an aerosoldelivery device and a formulation comprising a testosterone ortestosterone derivative (DHT) to be used either alone or in combinationwith any therapy already in use or currently under development to treatED including: phosphodiesterase (PDE) inhibitors (e.g., Viagra, Clalis),dopamine receptor agonists (e.g., apomorphine), melanocortin receptoragonists, intracavemous therapies (e.g., alprostadil, papaverine,phentolamine intracavernous therapies (e.g., alprostadil, papaverine,phentolamine, vasoactive intestinal peptide), growth hormone-releasingpeptide receptor agonists, 5-hydroxytryptamine (5-HT; serotonin)receptor agonists, alpha-adrenoceptor antagonists, topical therapies(e.g., alprostadil), guanylyl cyclase activators, rho-kinaseantagonists, oxytocin, oxytocin receptor agonists, and inhibitors ofneuropeptide Y.

It is an object of the invention to provide a kit comprising two aerosoldelivery devices and two formulations, a first formulation comprising atestosterone for use by women, and a second formulation comprising atestosterone, sildenafil-citrate or other salt of sildenafil, e.g.,acetate, or other composition, or a combination thereof, for use by aman.

These and other aspects, objects, advantages, and features of theinvention will become apparent to those skilled in the art upon readingthis disclosure.

DEFINITIONS

The terms “testosterone”, “a testosterone” and the like are usedinterchangeably here and are intended to mean the naturally occurringhormone known as testosterone having the chemical name17-β-hydroxyandrost-4-en-3-one which may be isolated and purified fromnature or synthetically produced in any manner. The terms also comprisepharmaceutically acceptable esters, i.e., compounds where the “H” of the“OH” group is replaced with an alkyl group, e.g., propionate, cypionateand enanthate. Other pharmaceutically acceptable derivatives includemethyltestosterone, methandrostenolone, fluovymesterone and danazol. Anumber of pharmaceutically useful derivatives of testosterone which areintended to be encompassed by the term testosterone as used here aredisclosed within the Physician's Desk Reference (most recent edition) aswell as Harrison's Principles of Internal Medicine. In addition,applicants refer to U.S. Pat. Nos. 5,536,714 issued Jul. 16, 1996;5,824,668 issued Oct. 20, 1998; 3,980,638 issued Sep. 14, 1996;4,031,117 issued Jun. 21, 1977; 4,085,202 issued Apr. 18, 1978;4,197,286 issued Apr. 8, 1980; 4,507,290 issued Mar. 26, 1985 and5,622,944 issued Apr. 22, 1997 all of which are incorporated herein byreference to disclose and describe testosterone derivatives andformulations.

The terms “reduced testosterone,” “dihydrotestosterone” and the like areused interchangeably here and are intended to encompass the commonlyoccurring reduced version of testosterone having been reduced by5α-reductase to 5α-dihydroxytestosterone which is also referred to hereas dihydrotestosterone (DHT) or simply “a testosterone.” Adihydrotestosterone may be isolated from nature but is preferablysynthetically produced and purified. Testosterone USP is a white orcreamy-white crystalline powder having a molecular weight of 288.43.

The terms “androgen,” “androgenic hormone” and the like are usedinterchangeably here and are intended to encompass any agent whichstimulates activity of the accessory male sex organs and specifically isintended here to cover “a testosterone” as well as a “reducedtestosterone” as defined above.

The terms “diameter”, “particle diameter” and the like are usedinterchangeably herein to refer to particle size as given in the“aerodynamic” size of the particle. The aerodynamic diameter is ameasurement of a particle of unit density that has the same terminalsedimentation velocity in air under normal atmospheric conditions as theparticle in question. This is pointed out in that it is difficult toaccurately measure the diameter of small particles using currenttechnology and the shape of such small particles may be continuallychanging. Thus, the diameter of one particle of material of a givendensity will be said to have the same diameter as another particle ofthe same material if the two particles have the same terminalsedimentation velocity in air under the same conditions. In connectionwith the present invention it is important to have particles which donot have too large of a diameter so that the particles can be inhaleddeeply into the lungs and thereby deposited on lung tissue andtransferred into the patient's circulatory system. It is equallyimportant not to have particles which are too small in that suchparticles would be inhaled into the lungs and then exhaled withoutdepositing on the lung tissue in the same manner that particles of smokecan be inhaled and exhaled with only a small amount of the particlesbeing deposited on the lung tissue. An acceptable range for particlediameter is in the range of 0.5 to 12 microns, preferably 0.5 to 8microns and more preferably 1 to 3 microns.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before the devices, formulations, and methodology of the presentinvention are described, it is to be understood that this invention isnot limited to the particular device, components, formulations andmethodology described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is with the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention which will be limited only by theappended claims.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “aformulation” includes mixtures of different formulations and referenceto “the method of treatment” includes reference to equivalent steps andmethods known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the invention, the preferred methods andmaterials are now described. All publications mentioned herein areincorporated herein by reference to describe and disclose specificinformation for which the reference was cited in connection with.

All publications mentioned herein are incorporated herein by referenceto described and disclose specific information for which the referencewas cited in connection with. The publications discussed herein areprovided solely for their stated disclosure prior to the filing date ofthe present application. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate suchpublications by virtue of prior invention. Further, the actualpublication date may be different from that stated on the publicationand as such may require independent verification of the actualpublication dates.

Some embodiments of the invention involve the bolus delivery oftestosterone or dihydrotestosterone. Thus, the invention is generallyand specifically described by referring to testosterone and/ordihyrotestosterone specifically. However, the invention is moregenerally applicable to any androgen.

Invention in General

Despite the fact that steady state delivery of testosterone asreplacement therapy for women experiencing decreased libido isinherently prone to producing unwanted side effects, the use ofpulsatile testosterone replacement therapy to mimic the normalelaboration of this hormone during ovulation has not been explored. Theuse of testosterone replacement therapy for brief courses of treatmenthas been attempted, however the slow rate of absorption of methyltestosterone from pills has limited its utility. In order to replace themissing testosterone in a therapeutically effective manner, it isnecessary to provide a rapid pulse of bioavailable testosterone to thepatient on demand. In this way, testosterone could be replaced by thepatient as needed coincident with the desire to engage in sexualactivity. Similarly, the current methods of delivery of testosterone tomen do not provide physiologically correct pharmacokinetics. Similarly,the current methods of delivery of testosterone and other compositionsfor the treatment of ED do not approximate endogenous, physiologicallycorrect pharmacokinetics.

It is not surprising that clinical studies evaluating the effect ofacute, on demand testosterone replacement therapy in women withdecreased libido have not been attempted. The only tool currentlyavailable for a true pulsatile, rapid onset replacement therapy isintravenous administration. Although preparations of testosteroneappropriate for intravenous administrations have been available for sometime, intravenous cannulation as the means for gaining access to thecirculation for the administration of testosterone on demand isinconsistent with the desire for women to be able to modulate theirlibido in concert with the course of their daily lives.

Precision delivery of small molecule drugs via the lung for systemiceffect is possible. An electronic inhaler capable of delivering a liquidformulated drug stored in a unit dose packages has been described.Devices and container formulations of solutions and suspensions to beaerosolized are described in U.S. Pat. Nos. 5,544,646; 5,718,222;6,123,068; 6,014,969; 5,660,166; and 5,823,178 as well as thepublications cited in these patents. Other types of aerosol deliverydevices which contain pressurized propellants can also be used, e.g.,see U.S. Pat. Nos. 5,404,871; 5,542,410; and 5,826,570 as well as thepublications cited in these patents. Nebulizers and dry powder inhalerdevices can also be used. A formulation of testosterone ordihydrotestosterone can be prepared for a bolus delivery including anaerosol delivery.

The quantitative delivery of testosterone or dihydrotestosterone, ondemand by a woman prior to initiation of sexual intercourse, provides amechanism for testosterone replacement therapy which is unlikely to beassociated with side effects precipitated by chronic delivery of thedrug. The present invention differs from most methods of treatment inthat the method taught here preferably obtains an effective increase intestosterone quickly and thereafter has the drug metabolized so thatthere is no longer an effect on the patient. Thus, while most drugs aredelivered to obtain a relatively constant therapeutic effect the methodof the present invention obtains a very short-term effect. In providinga useful method of increasing libido the patient's testosterone level ispreferably raised in 30 minutes or less or more preferably five minutesor less and is metabolized out of the patient's system to belowtherapeutic levels in four hours or less or preferably two hours orless.

Administration can be by a variety of different routes includingintravenous, intranasal, buccal, transdermal and intrapulmonary.However, intravenous injection can be an uncomfortable route ofadministration. Transdermal delivery is generally too slow but withpermeation enhancers and/or a large surface area one can obtain thedesired “bolus” administration. Creating an aerosol and delivery byinhalation is the preferred route of administration for convenience andquickly raising blood levels. Any two or more of these different routesof administration may be combined to enhance the desired effect.Further, one route of administration (e.g., transdermal) may be used toincrease basal levels over long term (below levels causing adverse sideeffects) while using another route (e.g., inhalation) to increase levelsmore quickly over a much shorter term to obtain the desired short termincrease in libido.

While particularly applicable to post menopausal woman, the use oftestosterone replacement therapy to modulate libido could be of value towomen still of child bearing age. Disappearance of or reduction of thelibido has been described in women who are continuing to ovulate. Thereduction in libido may be due to therapy including the use of birthcontrol pills which contain hormones. Therefore, acute administration oftestosterone to significantly raise blood levels for discrete periodshas potentially widespread application in women across a wide range ofages.

The baseline serum testosterone level of a normal adult human female isgenerally below about 1 ng/ml with modest changes through the menstrualcycle (Geobelmann et al., Am J. Obstet. Gynecol. 119:445 (1974)) withgeneral fluctuation between about 0.3 to 0.5 ng/ml. However, adult humanfemales with polycystic ovarian disease have ovarian vein testosteronelevels of 20 to 65 ng/ml and peripheral venous levels of about 7.5 ng/ml(Dupon et al., Am. J. Obstet. Gynecol. 115:478 (1973)). Abnormally highlevels of testosterone over long periods are associated with acne andhirsutism.

To maintain normal testosterone levels an adult human female willproduce about 0.25 mg of testosterone per day as compared to about 5-6mg/day produced by a normal adult male to maintain a normal adult maletestosterone level of 3 to 10 ng/ml. Because women produce such smallamounts of testosterone the administration of very small amounts willdramatically increase the patient's normal levels. In accordance withthe present invention 0.05 mg to 5 mg, preferably 0.25 to 2 mg and morepreferably about 1 mg of testosterone is administered to the circulatorysystem of the patient. Administration of such amounts to the circulatorysystem may require aerosolizing larger amounts due to inefficiencies inthe aerosol delivery system.

Testosterone can be administered orally. However, after oraladministration it is absorbed from the gut into the portal blood anddegraded promptly by the liver. Also, the absorption is relatively slow.Thus, insignificant amounts reach the patient's systemic circulation.Testosterone can also be administered parenterally but, because of itspoor aqueous solubility, alcoholic solutions generally are necessary.These alcohol-based formulations may cause unpleasant sensations at thesite of injection. Further, when so administered it is rapidly absorbedand metabolized making it difficult to sustain effective levels inplasma over time. In view of such, effective therapy has been carriedout using means of delivery where testosterone is slowly absorbed (e.g.,dermal patches) or when the testosterone is chemically modified toretard absorption and/or catabolism.

The present invention preferably uses intrapulmonary delivery to avoidfirst pass liver metabolism and to obtain quick infusion into thepatient's systemic circulatory system. Further, the method of thepresent invention does not require maintaining increased testosteronelevels over long periods. Accordingly, chemical modification to retardabsorption and/or catabolism are not required or desired.

The present invention administers sufficient testosterone by inhalationto temporarily raise the patient's libido, increase the patient'spropensity for orgasm, and thereafter allow the patient's testosteronelevel to return to a level normally experienced by the patient.

Therapies to Treat Erectile Dysfunction

Testosterone therapy as described herein can be used in combination withother therapies intended to increase or enhance libido. Such therapiesinclude but are not limited to herbal preparations and vitaminsupplements.

There are known methods and formulations for treating female sexualdysfunction (FSD) as well as male erectile dysfunction (ED). These knownmethods and formulations can be used in combination with orindependently of the bolus androgenic hormone delivery methodologydisclosed and described here.

Formulations and methods of treating ED include those disclosed anddescribed in U.S. Pat. Nos. 5,718,917; 6,156,753; 6,037,346; and6,007,824 which include oral and local administration of sildenafilcitrate. Other formulations and methods of treating ED are disclosed anddescribed in U.S. Patent Application Publication No. 2003/0171393 whichinclude the topical application of sildenafil salts where the salts areorganic salts, including but not limited to oxalate, tartrate, maleate,succinate, citrate, glycinate, lysinate, or inorganic anions includingbut not limited to nitrate, chloride, sulphate, phosphate. Otherpharmaceutically acceptable salts are disclosed in the Handbook ofPharmaceutical Salts: Properties, Selection, and Use; P. Heinrich Stahl,and Camille G. Wermuth, Eds.; Wiley VCH, Weinheim, Federal Republic ofGermany (2002); pp. 334-345.

Formulations and methods of treating FSD include those disclosed anddescribed in U.S. Pat. Nos. 6,046,240; 5,877,216; 5,891,915; 5,698,589;6,089,909; and 6,169,914 which include the administration ofvasodilating drugs to the vaginal area to increase blood flow to thatarea.

Indications

The method of the invention has broad applicability to both the male andfemale populations. However, its use is specifically indicated in sixcategories.

First, post-menopausal women who have experienced all or any of (1)decreased levels of testosterone; (2) decreased libido; and (3)decreased propensity to experience orgasm.

Second, women of child bearing age who have experienced all or any of(1) decreased levels of testosterone; (2) decreased libido; and (3)decreased propensity to experience orgasm.

Third, women of child bearing age being treated with birth control pillswho have experienced all or any of (1) increased levels of estrogenrelative to testosterone resulting in either or both of (2) decreasedlibido and (3) decreased propensity to experience orgasm.

Fourth, men with reduced libido.

Fifth, men having a decreased level of serum testosterone.

Sixth, men having erectile dysfunction.

In the first three categories it is not desirable to administersufficient amounts of a testosterone so as to raise the patient'stestosterone level continually over long periods of time. For example,it is not desirable to administer testosterone several times per day forseveral days. Such will raise testosterone levels over long periods andresult in adverse side effects including acne, and increased growth ofbody hair. Bolus delivery to men facilitates a more physiological meansof delivery of testosterone than that afforded by the currently marketedtransdermal patches.

Dosing

The amount of a testosterone administered will vary based on a factorsuch as the age, weight and baseline testosterone level of the patient.Initially, small doses, e.g. about 0.25 mg, is administered for women.If the desired result is obtained no further dosing is provided. If thedesired effect is not obtained additional 0.25 mg doses can beadministered up to 2.0 mg. If the patient finds that larger doses areneeded then for further treatment the patient may be provided with dosesof 0.5 mg, 1.0 mg or 2.0 mg. The amount aerosolized may be substantiallygreater than the amount administered if the interpulmonary deliverydevice is inefficient. Thus, the device and method efficiencies must betaken into consideration when titrating the doses.

When testosterone enters the circulatory system of a human patient it isreadily reduced via 5α-reductase to 5α-dihydrotestosterone. Thus, whenreferring to increasing a patient's testosterone level this disclosureis referring to combined levels of testosterone and5α-dihydroxytestosterone present in the patient's serum. The presentinvention includes the administration of 5α-dihydroxytestosterone whichis the active molecule. The invention also includes the administrationof testosterone derivatives provided such derivatives increase libidoand do not result in unacceptable adverse effects.

Obtaining a result such as increased libido may be difficult toascertain. Some placebo effect will be experienced by some patients andothers may continuously administer doses in an attempt to obtain a moreenhanced effect. To avoid undesirable side effects from overdosing orfrom dosing to frequently the delivery device may be controlled by asuitable lockout system such as taught in U.S. Pat. Nos. 5,507,277;5,694,919; and 5,735,263. Such a system can prevent release of more thana given amount of drug at a single dosing event and/or restrict thenumber of dosing events within a given period of time. The restrictionsare designed to prevent the patient from experiencing adverse secondaryeffects.

Formulations/Devices

Pharmaceutical grade testosterone can be produced as a white or creamywhite powder. The pure powder is aerosolized and inhaled by itself orwith the use of a dry powder inhaler (DPI) device. However, it isdesirable to formulate the crystals with an excipient to provide smallparticles of dry powder which do not stick together. Also, the doses oftestosterone can be so small (<1 mg) which would make filling andmetering of the doses difficult without blending testosterone with a“carrier” material such as lactose particles. The testosterone particlespreferably have an aerodynamic diameter in a range of from about 1 to 10microns more preferably 1 to 5 microns and still more preferably about 1to about 3 microns. Testosterone could be also dissolved in a suitablesolvent together with some excipients and then could be recovered assolid or porous particles by removal of the solvent e.g. by spraydrying, or freeze-drying or using precipitation followed by removal ofthe solvent. Methods of formulating dry powders and dry powder inhalerdevices are disclosed in U.S. Pat. Nos. 5,826,633; 5,814,607; 5,785,049;5,780,014; 5,775,320; 5,740,794; and Des. 390,651 all of which areincorporated by reference to describe and disclose such.

Testosterone, sildenifil citrate, and some other drugs for treatment ofED and SD are relatively insoluble in water. Accordingly, to create asolution a solubilizer (e.g., one of several cyclodextrines orphospholipids) or an organic solvent such as ethanol is used.Alternatively, a microsuspension in water with or without ethanol canalso be produced. The solution is aerosolized and inhaled. The solutioncan be placed in a low boiling point propellant in a pressurizedcanister and released using a conventional metered dose inhaler (MDI)device. Preferably, the MDI device is modified so that the aerosolizeddose is released each time at the same inspiratory flow rate andinspiratory volume. When this is done the patient is more likely toreceive the same dose each time. A device for obtaining repeatabledosing with an MDI canister is taught in U.S. Pat. No. 5,404,871 issuedApr. 11, 1995.

In accordance with the present invention it is preferable to load thesolution into a container which opens to a porous membrane. When theformulation is moved through the membrane it is aerosolized. Suchcontainers are taught in U.S. Pat. No. 5,497,763 issued Mar. 12, 1996.The container is loaded into a device and delivered via a method astaught in U.S. Pat. No. 5,823,178 issued Oct. 10, 1998 both of whichpatents are incorporated herein by reference to describe and disclosecontainers, devices and methods of drug delivery by inhalation.

Aerosol drug delivery devices vary but generally are comprised of (1) acontainer for the drug e.g. testosterone; (2) a means for aerosolizingthe drug; and (3) a mouthpiece from which the aerosol is inhaled. Theaerosol can be any small particles dispersed in air, e.g. a cloud of adry powder or a fine spray of liquid formulation. Nebulizers, metereddose inhalers (MDIs) and dry powder inhalers (DPIs) are the most wellknown devices for creating an aerosol. Less conventional devices knownas electrohydrodynamic aerosol devices as taught in U.S. Pat. No.4,358,059; PCT WO 99/07478; and 98/03267 can also be used to create anaerosol in the method of the invention.

Nasal or buccal formulations could be used for nasal or buccal delivery,or transdermal patches, preferably with absorption enhancers to achieve“bolus” delivery of testosterone into the blood stream.

Aerosol Administration of Sildenafil and Other Compositions

Similarly, agents such as sildenafil citrate and other salts ofsildenafil, e.g., sildenafil acetate (U.S. Pat. No. 5,426,107 and U.S.Pat. No. 5,250,534), or other compositions useful in the treatment of SDor ED can also be administered to women or men by the methods of theinstant invention, alone or in combination with testosterone.

Sildenafil citrate, also termed VIAGRA™, is typically administered intablet form to men experiencing erectile dysfunctions resulting fromperipheral vascular disease. The tablet is taken orally about thirty(30) minutes to four (4) hours before sexual activity.

The typical oral dose of sildenafil is 25-100 mg per day. As describedabove, such doses can be administered to the lungs through the use ofaerosolized aqueous solutions or as a dry powder. Because of the morerapid absorption from the lung, lower doses can be delivered to achievethe same effect, albeit for a shorter period of time.

The advantage of aerosolized delivery is a faster result as compared tooral administration. Further, the delivery of sildenafil citrate eitherorally or via an aerosol can be combined with the bolus delivery of atestosterone formulation.

The can be formulated alone or as an admixture with a testosterone forsimultaneous bolus delivery.

In an embodiment, men in need of supplemental testosterone andexperiencing erectile dysfunction can administer the drugs eithersimultaneously or sequentially. The dosage of testosterone willtypically be sufficient to raise the serum testosterone level of the manto a normal range, that being about 200-1000 ng/dL.

The formulation can be administered to male or female patients and maybe administered alone or in combination with an aerosolized dose oftestosterone.

In one embodiment of the invention the sildenafil citrate isadministered orally and the testosterone is administered by aerosolabout 30-60 minutes after the oral administration of sildenafil citrate.The oral administration of sildenafil citrate is an administration inadvance of a sexual event and after allowing time to achieve atherapeutic effect on increasing blood flow the patient is dosed withtestosterone via aerosol. The testosterone enhances the libido and thesildenafil citrate enhances the patient's ability to perform and/orachieve orgasm. The aerosolized administration of testosterone couldalso be in used combination with other drugs administered byaerosolization or by other means, e.g., alprostadil administeredtopically, used in the treatment of various sexual dysfunctions, e.g.,erectile dysfunction. Alternatively, such drugs may be deliveredaccording to the methods of the present invention as a monotherapy(i.e., without testosterone).

Examples of such fast-acting drugs for treating erectile dysfunctionwhich may be used according to the methods of the present inventioninclude but are not limited to PDE5 inhibitors, melanocortin receptors,oxytocin and oxytocin receptor agonists, inhibitors of a neuropeptide Y(NPY), dopamine receptor agonists (e.g., apomorphine), melanocortinreceptor agonists, intracavernous therapies, growth hormone-releasingpeptide receptor agonists, 5-hydroxytryptamine receptor agonists,alpha-adrenoceptor antagonists, topical therapies, guanylyl cyclaseactivators, and rho-kinase antagonists.

PDE5 inhibitors are known to treat erectile dysfunction as disclosed inU.S. Patent Application Publication No. 2003/0144296. PDE5 convertscyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate(cAMP) to monophosphate. cGMP is a major intracellular effector ofsmooth muscle relaxation, facilitates increased blood flow, and elicitserection. By reducing the breakdown of cGMP, PDE5 prolongs action ofcGMP. Vardenafil (Nuivi, Bayer/GSK) and Tadalfil (Clalis, Lilly ICOSLLC) are two PDE5 inhibitors that may be administered by the methods ofthe present invention. Vardenafil has been administered orally from 5 to20 mg, with onset of the therapeutic effect occurring at about 40minutes after administration and lasting for about 4 hours. Tadalafilhas been administered orally from 10 to 20 mg, with onset of thetherapeutic effect occurring at about 16 minutes after administrationand lasting up to about 36 hours.

In animal models, the α-melanocyte stimulating hormone (α-MSHs) and theadrenocorticotropic hormone (ACTH) induce erection, ejaculation,grooming, stretching, and yawning (Argiolas et al, Brain Res. Bull. 51:425-32, 2000). Most, if not all, activities of α-MSH/ACTH peptides aremediated through specific subtypes of the melanocortin (MC) receptors inthe hypothalamic periventricular region (Argiolas et al, Brain Res.Bull. 51: 425-32, 2000; Vergoni et al, Eur. J. Pharmacol. 362: 95-101,1998). It has recently been shown the MC4 receptor causes erection inrats. (Shadnick et al, Presentation at Society of Neuroscience, 2001).Melatonan 11/PT-141 (Palatin Technologies, Inc.) is a synthetic cyclicheptapeptide analog of α-MSH and is a nonselective MC receptor agonist.It is known to be a potent inducer of erection in men with non-organicED when injected subcutaneously; however, yawning and stretching, and insome cases severe nausea and vomiting limit is use (Wessells et al, Int.J. Impot. Res. 12 (Supp. 4): S74-S79, 2000). Intranasal administrationof this formulation, however, does not appear to exhibit these sideeffects. With a dose of 4-20 mg administered intranasally, therapeuticonset takes place in about 34-63 minutes of dosing and lasts for as longas 138 minutes (Diamond et al., Int. J. Impot. Res. 12 (Supp. 4):S20-21, 2002).

Oxytocin and 5-hydroxytryptamine (5-HT; serotonin) receptor agonists areother compounds known to induce erection in rats by increasing nitricoxide (NO) synthase and smooth muscle relaxation (Argiolas et al, Eur.J. Pharmacol. 130: 265-272, 1986; Hayes et al, Int. J. Impot. Res.12(Supp. 3): S62, 2000). However, there is currently no knowndevelopment of oxytocin or analogues thereof for treating ED.

Growth hormone (GH)-releasing peptide receptors also act by way of theoxytocinegic pathway to increase NO synthase and muscle relaxation. Anew class of peptides that release GH is more potent than endogenousGH-releasing hormone. Studies involving the injection of 20-200 ng intothe paraventricular nucleus of the hypothalamus in rats have inducederection indistinguishable from those of dopamine receptor agonists,oxytocin, or N-methyl-D-aspartic acid (Melis et al, Int. J. Impot. Res.12: 255-262, 2000).

Apomorphine, a dopamine D1 and D2 D₁ and D₂ receptor agonist, provides ashort-acting therapeutic effect although it has a narrow therapeuticwindow (Lal et al, Prog. Neuropsychopharmacol. Biol. Psychiatry 13:329-339, 1989). However, the duration of erectile response in rats hasbeen prolonged in combination with sildenafil (Andersson et al, J. Urol.161: 1707-12, 1999). A nasal form of apomorphine is being developed(Nastech) to treat male and female sexual dysfunction in humans.

α-adrenoceptor (AR) antagonists have the effect of blocking α₁-AR and/orα₂-AR on smooth muscle and thereby decreasing the sympathetic tone ofpenile erectile tissues, causing relaxation of the smooth muscle.Suitable AR antagonists include phentolamine mesylate (Vasomax® byZonagen), thymoxamine (moxisylyte), yohimbine (α2 antagonist). It hasbeen found that the nitrosylation of moxisylyte and yohimbine haveproduced more potent compounds (Saenz de Tejada et al., J. Pharmacol.Exp. Ther. 290: 121-128, 1999). Additionally, NitroMed is developingoral medications that combine the NO donor L-arginine and thealpha-blocker yohimbin to treat the full range (mild to severe) of EDsufferers.

The most commonly used intracavernous drug therapies in the U.S. areprostagladin E₁ (alpostadil) alone and in combination with papaverineand phentolamine (Trimex). Prostagladin E₁ increases intracellularconcentrations of cAMP in the corpus cavernosum, thereby enhancingvasodilation. While these drugs have been highly effective in treatingED, they have certain disadvantages including the requirement that theybe administered by injection and they carrying the risk of causingpriapism and scarring in the penis (Porst, J. Urol. 155:802-815, 1996;Fallon, Urol. Clin. North Am. 22: 833-845, 1995). Vasoactive intestinalpeptide_(VIP) is another intracavernous drug that is potent as a smoothmuscle relaxant with an onset between 2 to 5 minutes after dosing andlasting up to 2.5 hours (data cited at www.Senetek.com).

Guanylyl cyclases (GC) receptors are another type of formulation fortreating ED. GC exists in soluble (sGC) and particulate (GC-B) forms inall cell types, and helps to catalyze the conversion of GTP to cGMP.YC-1 (3-(5′-hydroxymethyl-2′furyl)-1-benzyl-indazole) directly activatessGC by increasing affinity for GTP leading to increased cGMP in smoothmuscle, which is the major intracellular effector of smooth musclerelaxation. Studies have shown that YC-1 administered intracavernouslyelicited dose-dependent erection in rats (Andersson and Hedlund Int. J.Impot. Res. 14(Supp1.1): S82-S92, 2002). BAY-41-2272 (pyrazolpyridine),another GC receptor, has been shown to cause relaxation of human andrabbit corpus carvemosum more potently than YC-1 by stimulating sGC inan NO-independent manner without relying upon cGMP breakdown (Kalsi etal, Int. J. Impot. Res. 14(Suppl. 3): S2, 2002).

Rho-kinase antagonists, such as Y-27632 (Mitsubishi Pharma, Osaka,Japan), applied topically stimulated erection in rats possibly byincreasing corpus caveronsum pressure. Specific inhibition of Rho-kinasein the cavemosal circulation leads to erection by a mechanism notdependent on NO-cGMP signaling (Nature Medicine, 7:119, 2001).

Depending on the type of drug, the dosage required, the time oftherapeutic onset and the duration of such therapeutic onset will vary.The dosages required for aerosolized delivery are likely to be less thanthose indicated for oral delivery.

Other oral, injectable and topical drugs are and will become availablefor the treatment of sexual dysfunctions and such drugs (e.g.,vasodilators) can be used in combination with aerosolized delivery oftestosterone to obtain enhanced results. It is noted that although suchdrugs may, by themselves, facilitate sexual activity they do not affectlibido. Accordingly, a truly enhanced effect is obtainable by combininga drug, which increases blood flow to a desired area, with aerosolizeddelivery of testosterone, which increases libido.

Kits

In an embodiment of the invention, a kit is provided for use by ahealthcare provider, and more preferably for use by a patient. Anexemplary kit will provide a hand-held aerosol delivery device and atleast one dose, preferably one to about one hundred, more preferably oneto thirty doses of a testosterone for use by a women. In an embodiment,the kit will comprise a hand-held aerosol delivery device and at leastone dose, preferably one to about one hundred, more preferably one tothirty doses of a testosterone for use by a man. In an embodiment, thekit will provide a hand-held aerosol delivery device and at least ondose, preferably one to about one hundred, more preferably one to thirtydoses of an admixture of testosterone and sildenafil citrate for use bya man. In an embodiment, the kit will contain a hand-held aerosoldelivery device and at least one dose, preferably one to about onehundred, more preferably about one to thirty doses of sildenafil citratefor use by a man.

In an embodiment, a kit is provided which comprises two hand-helddelivery devices, wherein a first delivery device comprises at least onedose, preferably one to one hundred doses, of a testosterone for use bya woman. The second delivery device comprises at least one dose,preferably one to one hundred doses, of a testosterone, sildenafilcitrate, or a combination thereof for use by a man. Such a kit isintended for use by a couple in need of such treatment.

The kit of the invention can be comprised of various combinations ofdrugs and drug delivery devices. However, the kit will preferably becomprised of an aerosol drug delivery device which comprises a containerwhich holds one or a plurality of doses of testosterone, a means foraerosolizing the testosterone and a mouthpiece from which theaerosolized testosterone may be inhaled. This device is present in thekit with another drug. For example, the kit may comprise a container ofsildenafil citrate or related drug which obtains a response similar tosildenafil citrate. The other drug may be administered orally ortopically but is preferably in a container which can be loaded into thedevice used to deliver the testosterone by inhalation. Thus, a preferredkit will comprise a drug delivery device which can generate an aerosolfor inhalation and a plurality of containers of testosterone which canbe loaded into the device and a plurality of containers of a vasodilatorsuch as sildenafil citrate which can be loaded into the device.

The instant invention is shown and described herein in a manner which isconsidered to be the most practical and preferred embodiments. It isrecognized, however, that departures may be made therefrom which arewithin the scope of the invention and that obvious modifications willoccur to one skilled in the art upon reading this disclosure.

1.-18. (canceled)
 19. A kit for the treatment of erectile dysfunction ina man, comprising: a hand-held device for the aerosolized delivery of aformulation; a container of an aerosolizable formulation comprising aphosphodiesterase (PDE) inhibitor.
 20. The kit of claim 19, furthercomprising: a plurality of containers of aerosolizable formulation of aphosphodiesterase (PDE) inhibitor.
 21. The kit of claim 19, furthercomprising: instructions for administering the formulation to treaterectile dysfunction.
 22. The kit of claim 20, wherein each of thecontainers of a phosphodiesterase (PDE) inhibitor comprises 25 mg ofaerosolizable phosphodiesterase (PDE) inhibitor.
 23. The kit of claim20, wherein each of the containers of a phosphodiesterase (PDE)inhibitor comprises 25 mg to 100 mg of aerosolizable phosphodiesterase(PDE) inhibitor.
 24. The kit of claim 19, comprising from 1 to 100containers of aerosolizable formulation of a phosphodiesterase (PDE)inhibitor.
 25. The kit of claim 19, comprising from 1 to 30 containersof aerosolizable formulation of a phosphodiesterase (PDE) inhibitor. 26.The kit of claim 19, wherein the formulation is a liquid formulation.27. The kit of claim 19, wherein the formulation is a dry powder. 28.The kit of claim 19, wherein the formulation comprises a pressurizedpropellant.
 29. A kit, comprising: a plurality of containers of aformulation for pulmonary delivery, the formulation comprising aphosphodiesterase (PDE) inhibitor; and instructions for administeringthe formulation to treat erectile dysfunction.
 30. The kit of claim 29,wherein the phosphodiesterase (PDE) inhibitor is chosen from Viagra andClalis.
 31. The kit of claim 29, wherein the formulation is a liquidformulation.
 32. The kit of claim 29, wherein the formulation is a drypowder.
 33. The kit of claim 29, wherein the formulation comprises apressurized propellant.
 34. A method of treating erectile dysfunction,comprising: aerosolizing a formulation comprising a phosphodiesterase(PDE) inhibitor; inhaling the aerosolized formulation comprised of aphosphodiesterase (PDE) inhibitor into lungs of a patient to be treatedfor erectile dysfunction; allowing particles comprised of aphosphodiesterase (PDE) inhibitor to deposit on lungs of the patient andenter the patient's circulatory system.
 35. The method of claim 34,wherein the formulation is a liquid formulation.
 36. The method of claim34, wherein the formulation is a dry powder.
 37. The method of claim 34,wherein the formulation comprises a pressurized propellant.
 38. A kitfor the treatment of erectile dysfunction in a man, comprising: ahand-held device for the aerosolized delivery of a formulation; acontainer of an aerosolizable formulation comprising a compound chosenfrom a dopamine receptor agonist, a melanocortin receptor agonist, agrowth hormone-releasing peptide receptor agonist, and analpha-adrenoceptor antagonist.
 39. The kit of claim 38, furthercomprising: a plurality of containers of aerosolizable formulation of acompound chosen from a dopamine receptor agonist, a melanocortinreceptor agonist, a growth hormone-releasing peptide receptor agonist,and an alpha-adrenoceptor antagonist.
 40. The kit of claim 38, furthercomprising: instructions for administering the formulation to treaterectile dysfunction.
 41. A method of treating erectile dysfunction,comprising: aerosolizing a formulation comprising a drug which is acompound chosen from a dopamine receptor agonist, a melanocortinreceptor agonist, a growth hormone-releasing peptide receptor agonist,and an alpha-adrenoceptor antagonist; inhaling the aerosolizedformulation comprised of the drug into lungs of a patient to be treatedfor erectile dysfunction; allowing particles comprised of the drug todeposit on lungs of the patient and enter the patient's circulatorysystem.
 42. The method of claim 41, wherein the formulation is a liquidformulation.
 43. The method of claim 41, wherein the formulation is adry powder.